Glucuronic acid pathway role

in biotransformation, vitamin

c synthesis and extracellular

matrix. By-Beruk Ketema

AAU, School of medicine

Group 2, section 5

May 2014

objectives

What is Glucouronic acid?What is Glucuronic acid path way?Relation between Glucuronic acid and Vitamin c synthesis.Use Glucuronic acid in Biotransformation.Advantages of Glucuronic acid pathway.

What is Glucouronic acid.

Glucouronic acid (from ancient Greek gluco-sweet, uronic-urine) is a carboxylic acid.

Its structure is similar to that of glucose. However, glucouronic acid’s sixth carbon is

oxidized to a carboxylic acid. Its formula is C6H12O7.

The salts and ester of glucuronic are known as

glucuronates; the anion C6H12O7 is glucuronates ion.

Glucuronic acid should not be confused with gluconic

acid, a linear carboxylic acid resulting from the

oxidation of a different carbon of glucose.

Gluconic acid a crystalline acid C6H12O7 obtained by

oxidation of glucose and used chiefly in cleaning

metals and as the source of its salts some of which are

used medicinally.

CONT…….

Glucuronic acid is common in carbohydrate chains of

proteoglycans. It is part of mucous animal secretions

(such as saliva), cell glycocalyx, and intercellular

matrix (for instance hyaluronan).

Molecular property

Molecular formula ----- C6H12O7

Molecular mass---------194.14 g/ mol

Melting point------------159-161℃

What is Glucuronic acid path way?

The conversion of UDP-glucuronates to glucuronates, usually thought to proceed by way of glucuronates 1-phosphate , is a site for short-term regulation of vitamin C synthesis by metyrapone and other xenobiotics in isolated rat hepatocytes

The formation of glucuronate from UDP-glucuronate in liver extracts enriched with ATP-Mg, but did not affect the formation of glucuronate 1-phosphate from UDP-glucuronate or the conversion of glucuronate 1-phosphate to glucuronate. This and other data indicated that glucuronate 1-phosphate is not an intermediate in glucuronate formation from UDP-glucuronate, suggesting that this reaction is catalyzed by a 'UDP-glucuronidase'. UDP-glucuronidase was present mainly in the microsomal fraction, where its activity was stimulated by UDP-N-acetylglucosamine, known to stimulate UDP-glucuronosyltransferases by enhancing the transport of UDP-glucuronate across the endoplasmic reticulum membrane.

CONT….

. UDP-glucuronidase and UDP-glucuronosyltransferases displayed similar sensitivities to various detergents, which stimulated at low concentrations and generally inhibited at higher concentrations. Substrates of Glucuronidation inhibited UDP-glucuronidase activity, suggesting that the latter is contributed by UDP-glucuronosyltransferases(s). Inhibitors of beta-glucuronidase and esterase’s did not affect the formation of glucuronate, arguing against the involvement of a glucuronidation-deglucuronidation cycle. The sensitivity of UDP-glucuronidase to metyrapone and other stimulatory xenobiotics was lost in washed microsomes, even in the presence of ATP-Mg, but it could be restored by adding a heated liver high-speed supernatant or CoASH. In conclusion, glucuronate formation in liver is catalyzed by a UDP-glucuronidase which is closely related to UDP-glucuronosyltransferases. Metyrapone and other xenobiotics stimulate UDP-glucuronidase by antagonizing the inhibition exerted, presumably indirectly, by a combination of ATP-Mg and CoASH.

Relation between Glucuronic acid and Vitamin c synthesis.

Vitamin C, a reducing agent and antioxidant, is a cofactor in reactions catalyzed by Cu(+)-dependent monooxygenases and Fe(2+)-dependent dioxygenases

It is synthesized, in vertebrates having this capacity, from d-glucuronate. The latter is formed through direct hydrolysis of uridine diphosphate (UDP)-glucuronate by enzyme(s) bound to the endoplasmic reticulum membrane, sharing many properties with, and most likely identical to, UDP-glucuronosyltransferases.

Glucuronate is converted to l-gulonate by aldehyde reductase, an enzyme of the aldo-keto reductase superfamily. l-Gulonate is converted to l-gulonolactone by a lactonase identified as SMP30 or regucalcin, whose absence in mice leads to vitamin C deficiency.

The last step in the pathway of vitamin C synthesis is the oxidation of l-gulonolactoneto l-ascorbic acid by l-gulonolactone oxidase, an enzyme associated with the endoplasmic reticulum membrane and deficient in man, guinea pig and other species due to mutations in its gene.

Cont.…. Another fate of glucuronate is its conversion to d-xylulose in a five-step pathway,

the pentose pathway, involving identified oxidoreductases and an unknown decarboxylase.

Semidehydroascorbate, a major oxidation product of vitamin C, is reconverted to ascorbate in the cytosol by cytochrome b(5) reductase and thioredoxin reductase in reactions involving NADH and NADPH, respectively. Trans membrane electron transfer systems using ascorbate or NADH as electron donors serve to reduce Semidehydroascorbate present in neuroendocrine secretory vesicles and in the extracellular medium. Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. The degradation of vitamin C in mammals is initiated by the hydrolysis of dehydroascorbate to 2,3-diketo-l-gulonate, which is spontaneously degraded to oxalate, CO(2) and l-erythrulose. This is at variance with bacteria such as Escherichia coli, which have enzymatic degradation pathways for ascorbate and probably also dehydroascorbate.

Most animals like guinea pig, bats, birds, and humans cannot synthesis vitamin c in their body due to absence of gulonoacetone oxidase enzyme, that is why ascorbic acid or vitamin c is a dietary requirement for humans.

Relation between Glucuronic acid and Biotransformation.

Biotransformation is the chemical modification (or

modifications) made by an organism on a chemical

compound. If this modification ends in mineral

compounds like CO2, NH4+, or H2O, the

biotransformation is called mineralization.Biotransformation means chemical alteration of

chemicals such as (but not limited to) nutrients,

amino acids, toxins, and drugs in the body. It is also

needed to render nonpolar compounds polar so that

they are not reabsorbed in renal tubules and are

excreted. Biotransformation of xenobiotics can

dominate toxicokinetics and the metabolites may

reach higher concentrations in organisms than their

parent compounds.Xenobiotics is a chemical compound (as a drug,

pesticide, or carcinogen) that is foreign to a living

organism.

CONT….

The metabolism of a drug or toxin in a body is an example of a biotransformation. The body typically deals with a foreign compound by making it more water-soluble, to increase the rate of its excretion through the urine. There are many different process that can occur; the pathways of drug metabolism can be divided into: 2 phases

Phase І reaction

Includes oxidative, reductive, and hydrolytic reactions.

In these type of reactions, a polar group is either introduced or unmasked, so the drug molecule becomes more water-soluble and can be excreted.

Reactions are non-synthetic in nature and in general produce a more water-soluble and less active metabolites.

CONT….

Phase II reactionThese reactions involve covalent attachment of small polar endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds.This is also known as a conjugation reaction.The final compounds have a larger molecular weight

Advantages of Glucuronic acid pathway.

1) Detoxification by Glucuronidation

2) Product of ascorbic acid or vitamin c in some vertebrates.

3) It is a major component of GAGs and Proteoglycans, so its main component

of extracellular matrix.

References

Wikipedia

Harpers biochemistry

Fundamental biochemistry

Functional biochemistry

WWW.NCBI.COM

LOURDES ALMAN RESEARCH